The long range goal of this research is to understand the cellular mechanisms by which associations are made during learning and by which neuronaI function is then altered. The marine snail Aplysia has provided an advantageous model system for the analysis of simple forms of learning because its nervous system consists of relatively few neurons, which are large and uniquely identifiable. Classical conditioning of the defensive withdrawal reflex of Aplysia resembles conditioning in vertebrates in a number of respects. Studies of conditioning in this system have demonstrated that during learning relationships between stimuli or events are detected by molecules within individual nerve cells. An associative form of neural plasticity, associative activity-dependent synaptic facilitation, occurs within the sensory neurons of the conditioning stimulus pathway, and contributes to the behavioral changes produced by conditioning. Within these sensory neurons, during associative facilitation, a dually- regulated enzyme, the calcium/calmodulin-sensitive adenylyl cyclase provides a molecular site of associative stimulus convergence. Calcium influx during a sensory neuron's activity provides a cellular representation of the conditioned stimulus; modulatory transmitter provides a cellular signal representing the unconditioned stimulus. The intracellular messenger cyclic AMP, which is synthesized by adenylyl cyclase participates in triggering the processes that strengthen the synaptic connections from the sensory neurons. Activation of the adenylyl cyclase by a brief exposure to modulatory transmitter is enhanced when the transmitter is immediately preceded by a increase in calcium. Furthermore, when calcium and modulatory transmitter are paired, the cyclase displays a sequence preference that parallels, and may underlie, the sequence preference of conditioning that the conditioned stimulus precede the unconditioned stimulus during training. One aim of this research is to analyze the molecular mechanisms responsible for this associative neural integration. This research will also investigate the mechanisms by which signaling from the sensory neurons is enhanced during both nonassociative and associative learning. The roles of intracellular messengers, including cyclic AMP, in initiating neuronal changes will be explored. The importance of neuronal changes due to modulation of ionic currents will be investigated, including a change in action potential shape and an increase in the reliability with which peripherally initiated sensory signals propagate in sensory neuron axons to central synaptic terminals. These studies may be important in understanding processes of recovery after peripheral injury, as well as basic mechanisms of learning.